Immunotherapy for the treatment of cancer includes multiple basic strategies. Four particular immunotherapy approaches have garnered a significant amount of scientific attention and clinical interest. First is the use of general agents including cytokines such as interleukin-2 (IL-2) to stimulate the immune system of the patient. However, this method is limited by the toxicity of IL-2. Second is the use of vaccines to promote a specific immune response to a target antigen present on tumors, and preferably not present on normal cells. Antigens include whole cells, proteins, peptides or a wide variety of immunizing vectors. Such methods are under active investigation. Current studies have focused on improving response by adding additional factors to enhance the immune response. Third is the use of antibodies capable of binding various cell or tumor-specific antigens and coupled to various toxins. These reagents can, in certain settings, deplete cancer cells. Other antibody therapies are directed at targeting inhibitory molecule in T cells, which might be inhibiting a T cell response to a cancer. Fourth, some have used T cells expressing an appropriate T-cell receptor that binds to the specific target antigen to promote an immune response, known as adoptive cell therapy (ACT). This approach involves the identification ex vivo of autologous or allogeneic lymphocytes with anti-tumor activity which are then infused into cancer patients, often along with appropriate growth factors to stimulate their survival and expansion in vivo.
ACT has substantial theoretical and practical advantages over the approaches discussed above. It is necessary to identify only a small number of anti-tumor cells with the appropriate properties that can then be expanded to large numbers ex vivo for treatment. Alternatively, by identifying T-cell receptors (TCRs) that bind to the tumor antigens, expression constructs can be inserted into T-cells from the patient to be treated. In vitro tests can identify the exact populations and effector functions required for cancer regression, which can then be selected for expansion. Similar strategies can be used for the treatment of viral infection, particularly chronic viral infection, by identifying TCRs that bind viral antigens (e.g., from Epstein Barr virus, herpes virus, human immunodeficiency virus). Such therapies can be used in conjunction with more traditional therapies.
ACT has been highly successful in the treatment of melanoma. Patients with metastatic melanoma have a median survival of about 8 months with a two year survival rate of about 10-15% with the two approved treatments from the FDA, IL-2 and dacarbazine. Using transfer of autologous tumor-infiltrating lymphocytes (TIL) after lymphodepleting chemotherapy resulted in objective responses in 51% of 35 heavily pretreated patients with metastatic melanoma. (Dudley M E, et al. Cancer regression and autoimmunity in patients following clonal repopulation with anti-tumor lymphocytes. Science 2002; 298:850-854; Dudley M E, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol 2005; 23:2346-2357). Further studies have confirmed the efficacy of the method of treatment of metastatic melanoma, particularly with myeloablating and lymphodepleting methods (Dudley, M E et al., Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens, J. Clin. Oncol. 2008; 5233-5239).
Treatment of melanoma using ACT has been successful at least in part due to the ability to identify autologous T-cells that react with MART-1 (Melanoma Antigen Recognized by T cells), and the subsequent cloning of T-cell receptors (TCR) that bind to MART-1. However, identification of T-cells having a high avidity for the desired antigen has proven to be a challenge as many of the tumor antigens are expressed during development or in one or more tissues in the body. Therefore, the T-cells expressing the appropriate TCR were likely deleted during clonal selection. Methods for cloning of TCRs for binding specific antigens have been established (see, e.g., Dossett. M L et al., Adoptive immunotherapy of disseminated leukemia with TCR-transduced, CD8+ T cells expressing a known endogenous TCR. Mol. Ther. 2009; 17:742-749). Such methods can include the cloning of an appropriate TCR from a non-human species, followed by alanine scanning, and subsequent mutational analysis to identify a TCR with higher affinity or efficacy that could be transduced into a T-cell for use in ACT (Parkhurst, M. R. et al., Characterization of genetically modified T-cell receptors that recognize the CEA:691-699 peptide in the context of HLA-A2.1 on human colorectal cancer cells. Clin. Cancer Res. 2009; 15:169-180). However, even after administration of T-cells expressing TCRs with high avidity for their target antigen, such cells can become inhibited or inactivated for reasons that are not presently understood.